PROJECT SUMMARY/ABSTRACT Retinopathy of prematurity (ROP) is a major cause of blindness and disability in children. With advances in neonatal care, smaller and more premature infants are saved who are at high risk for ROP. Therefore, the incidence of ROP continues to increase. Ablation surgery destroys retina and anti-Vascular endothelial growth factor (VEGF) treatment may cause systemic suppression of vessel growth in fragile neonates. The long-term goal is to understand the molecular mechanisms of ROP development to devise earlier preventative therapies. Inflammation and changes in immune function are clearly involved in ROP, but standard anti-inflammatory drugs such as steroids or NSAIDS are not effective in ROP and the way to control inflammation is not clear. However, immune cells are a source of cytokines and growth factors that may interact with the endothelial cells and contribute to the development of structural and functional abnormalities of the vessel wall. There is increasing evidence for the critical role of myeloid cells in retinal vascular development, remodeling, repair, and anastomosis. Myeloid cells such as microglia, are rapidly activated after an inflammatory insult and modulate angiogenesis. The overall objective in this application is to identify the mechanism of immune-vascular interaction in retinopathy. Understanding of pathological immune changes in the retinopathy is currently limited by a relative paucity of information about the physiology and function of resident immune cells in the healthy eye. Suppressor of cytokine signaling 3 (SOCS3) is a critical regulator that controls innate and adaptive immunity, tissue inflammation, cytokine production, and macrophage polarization, we reported that SOCS3 can suppress pathological ocular angiogenesis, therefore, SOCS3 is an essential immune-regulator that mediates immune-vascular interaction in ocular neovascularization formation. We found loss of SOCS3 in immune cells of myeloid origin significantly increased pathological retinal neovascularization in oxygen-induced retinopathy modeling ROP. We hypothesize that myeloid SOCS3 regulates immune-vascular crosstalk through modulating retinal inflammation, immune cell activation and recruitment to control retinopathy. The rationale for the proposed research is that understanding the molecular mechanisms of ROP development has the potential to develop treatment of ROP that now affects ~16,000 US infants per year. We will test this hypothesis with three Aims. Aim 1: To determine if myeloid SOCS3 controls pathological retinopathy; Aim 2: To determine if myeloid SOCS3 controls retinopathy through modulating the recruitment and activation of immune cells into the retina; Aim 3: To determine if myeloid SOCS3 controls immune-vascular crosstalk through modulation of retinal inflammatory proteins. The proposed research is innovative because it represents a substantive departure from the status quo by identifying the molecular mechanisms of immune-vascular crosstalk to control pathological retinopathy. The proposed research is significant because it will provide a novel target (SOCS3/immune-vascular crosstalk) for developing therapeutic strategies that have broad translational importance in the prevention and treatment of ROP and a wide range of other vascular eye diseases.